daunorubicinol and Leukemia

Levels of plasma daunorubicin, daunorubicinol and aglycone metabolites were measured in 47 patients 3 h after daunorubicin was administered daily for three days as part of a cytosine arabinoside/daunorubicin remission induction regimen. High-pressure liquid chromatography with fluorescence detection was used for separation and quantitation of the drug and its metabolites. A wide range of plasma levels were observed regardless of the outcome of therapy. Patients who had high levels of the drug, or daunorubicinol on day 1 of therapy tended to have high levels on days 2 and 3 of the regimen. Three hours after the third daily dose of daunorubicin was administered, patients who would not enter remission had significantly higher levels of aglycone metabolites in plasma than did patients who entered remission. These data indicate that resistance to chemotherapeutic effects of daunorubicin may be connected with metabolism of the drug, especially with enhanced metabolism to aglycones.

Topics: Acute Disease; Biotransformation; Daunorubicin; Humans; Injections, Intravenous; Kinetics; Leukemia; Naphthacenes

Leukemia cells isolated from eight patients with acute leukemia before treatment were examined for in vitro uptake of daunorubicin (DNR) and inhibition of DNA synthesis. In addition, plasma and cellular levels of DNR and daunorubicinol (DOL) were examined in six of the eight patients. Inhibition of DNA synthesis was determined with a 3H-thymidine incorporation assay. In vitro cellular 14C-DNR was quantified by means of liquid scintillation spectrometry, whereas in vivo DNR and DOL concentrations were determined by high-performance liquid chromatography. In vitro intracellular plateau concentrations of DNR were achieved within 1-2 h after continuous exposure to 0.01, 0.1, and 1.0 microgram/ml in the majority of cases. Based on our in vitro studies, a dose-response curve was found between increasing intracellular DNR and incorporation of 3H-thymidine. Peak intracellular levels of DNR after treatment occurred immediately after administration of the drug, whereas intracellular DOL levels accumulated over several hours. Plasma concentrations of DNR and DOL were not useful in estimating target tissue concentrations or inhibition of 3H-thymidine incorporation. Extrapolation of in vivo cellular DNR concentrations to the in vitro dose-response curve allows an estimate of DNR sensitivity.

Topics: Adolescent; Adult; Aged; Biological Transport; Cells, Cultured; Daunorubicin; DNA Replication; DNA, Neoplasm; Female; Humans; Leukemia; Male; Middle Aged

A selective and sensitive high-performance liquid chromatographic method was developed for the separation and quantitation of daunorubicin and its metabolites in serum, plasma, and other biological fluids. Daunorubicin and metabolites in human plasma were injected directly into the high-performance liquid chromatography system via a loop-column to pre-extract the drugs from the plasma, and quantitated against a multilevel calibration curve with adriamycin as the internal standard. The column effluent was monitored with an electrochemical detector at an applied oxidative potential of 0.65 V and by fluorescence. Daunorubicin and four metabolites were separated and characterized by this method. In a blinded evaluation of accuracy and precision, the mean coefficients of variation were 3.8, 3.6 and 9.8% at concentrations of 150, 75 and 15 ng/ml, respectively, and blank samples gave negligible readings. The amperometric sensitivity was greater than achieved by fluorescence detection, and offers an alternative method for quantitation of these compounds. The new method has a limit of detection of less than 2 ng on column, allowing quantitation of less than 10 ng/ml in plasma samples without organic extraction prior to chromatographic analysis.

Topics: Chromatography, High Pressure Liquid; Daunorubicin; Electrochemistry; Humans; Leukemia; Spectrometry, Fluorescence; Time Factors

Topics: Antibiotics, Antineoplastic; Daunorubicin; DNA; Humans; Kinetics; Leukemia; Naphthacenes; Oxidation-Reduction; Tissue Distribution

A method is given for the determination of daunorubicin and its main metabolite, daunorubicinol, in plasma from leukemic patients after administration of daunorubicin as the free drug or as a complex with DNA. Daunorubicin and daunorubicinol are extracted from 2 ml of plasma (pH 8.1) using a mixture of chloroform and 1-heptanol (9:1). After re-extraction into phosphoric acid (0.1 M), the separation is performed as reversed phase liquid chromatography on a LiChrosorb RP-2 (5 micrometer) column with a mobile phase of acetonitrile-water, acidified with phosphoric acid. The precision, by quantitation with a photometric detector, was better than 2% within the range 20 ng/ml to 200 ng/ml. Some determinations of plasma levels of daunorubicin and daunorubicinol are presented.

Topics: Chromatography, Gas; Daunorubicin; Dose-Response Relationship, Drug; Leukemia; Solvents